Agents for relieving side effects of adrenal cortex hormone

ABSTRACT

A medicament for reducing side effects of adrenocortical hormones comprising a phosphodiester compound of the following formula or a pharmacologically acceptable salt thereof                    
     wherein R 1  and R 2  are the same or different and each denotes hydrogen or methyl.

This is a 371 of PCT/JP99/03025 filed Jun. 4, 1999.

TECHNICAL FIELD

The present invention relates to a useful medicament for reducing sideeffects of adrenocortical hormones. More specifically, the presentinvention relates to a medicament for reducing side effects ofadrenocortical hormones which medicament comprises a certainphosphodiester compound constructed from ascorbic acid and tocopherol ora pharmacologically acceptable salt of the compound.

BACKGROUND ART

It is known that adrenocortical hormones, though not having a directinhibitory effect on phospholipase A₂, secondarily exhibitsanti-inflammatory effects by inducing production of an anti-inflammatoryprotein within the cells. However, there is a problem of great clinicalimportance that an extended use of adrenocortical hormones at high dosescauses serious side effects including reduction of glucose tolerance,aggravation of infections, delayed healing of wounds, formation ofsteroid cataract and induction of glaucoma. Thus, to separate the sideeffects of adrenocortical hormones from their therapeutic effects ishighly desired.

In order to separate the side effects from the therapeutic effects,which are both aspects of the adrenocortical hormonal effects,therefore, agents with adrenocortical hormonal effects must not beoverdosed. It is thus considered important to find an adjuvant moleculethat can augment adrenocortical hormonal effects, in particular, anadjuvant molecule that can augment adrenocortical hormones-mediated geneexpression.

No agent, however, has been known so far to serve as as an adjuvantmolecule that is safe and capable of augmenting adrenocorticalhormones-mediated gene expression, and there has been a need for anagent that can augment adrenocortical hormonal effects.

Thus, a study was carried out that was directed to reducing the sideeffects of adrenocortical hormones by combining them with another,adjuvant molecule, thereby allowing to lower the concentration ofadrenocortical hormones. The study revealed that a certain group ofphosphodiester compounds were capable of augmenting adrenocorticalhormonal effects (Japanese Unexamined Patent Publication No.H09-194376).

Upon the above background, however, the present inventors, from adifferent viewpoint, pursued a study in search of an agent that candirectly reduce the side effects of adrenocortical hormones not byreducing their dose (or their concentration in a preparation). In theprocess, the above phosphodiester compounds were further studied ontheir interaction with adrenocortical hormones. As a result, it wassurprisingly found by the present inventors that those phosphodiestercompounds and adrenocortical hormones, when concurrently administered,exhibit a synergism of the antiinflammatory effects of the respectiveagents, as opposed to simple addition of their effects. At the sametime, it was also unexpectedly found that the side effects of theadrenocortical hormones were directly and remarkably reduced. Thepresent invention was made upon this findings.

DISCLOSURE OF INVENTION

The present invention relates to:

(1) a medicament for reducing side effects of adrenocortical hormonescomprising a phosphodiester compound of the following formula or apharmacologically acceptable salt thereof

wherein R₁ and R₂ are the same or different and each denotes hydrogen ormethyl (hereinafter referred to as “the present compound”),

(2) the medicament for reducing side effects of adrenocortical hormonesaccording to (1) above, wherein the ratio of doses or concentrations ina preparation is 1 mg-100 mg of the phosphodiester compound or apharmacologically acceptable salt thereof to 1 mg of an adrenocorticalhormone,

(3) the medicament for reducing side effects of adrenocortical hormonesaccording to (1) or (2) above, wherein the adrenocortical hormone is acompound selected from the group consisting of betamethasone valerate,hydrocortisone, sodium dexamethasone meta-sulfobenzoate, triamcinoloneacetonide, alclometasone propionate, and fluocinolone acetonide, and

(4) the medicament for reducing side effects of adrenocortical hormonesaccording to (1) to (3) above, wherein the preparation form thereof isointment or eye drops.

DETAILED DESCRIPTION OF THE INVENTION

The medicament for reducing side effects of adrenocortical hormones ofthe present invention can be used as a medicament for reducing sideeffects of adrenocortical hormones, which have a wide variety of effectsincluding, e.g., antiinflammatory effect and adrenal cortex dysfunctiontreatment effect. Examples of adrenocortical hormones include, but arenot limited to, betamethasone valerate, hydrocortisone, sodiumdexamethasone meta-sulfobenzoate, triamcinolone acetonide, alclometasonepropionate, and fluocinolone acetonide.

The present compound used for a medicament for reducing side effects ofadrenocortical hormones can be synthesized by or according to the methoddescribed in, e.g., Japanese Patent Publication No. H02-44478 orJapanese Unexamined Patent Publication No. S62-205091.

A variety of uses are already known for the present compound used for amedicament for reducing side effects of adrenocortical hormones,including uses as anticataract medicaments, medicaments for preventionand treatment of climacteric disturbance, cosmetics havingskin-beautifying effect [Japanese Patent Publication No. H02-44478],anti-ulcer medicaments [Japanese Unexamined Patent Publication No.S63-270626], and medicaments for prevention and treatment of ischemicdisorders of organs [Japanese Unexamined Patent Publication No.H02-111722].

In addition, the present compound is known to directly inhibit anenzyme, phospholipase A₂, to thereby exhibit anti-inflammatory effects(Japanese Patent Publication Nos. H01-27044 and H05-23274). As notedabove, a further use is also known for the present compound as amedicament for augmenting adrenocortical hormonal effects (JapaneseUnexamined Patent Publication No. H09-194376). However, this JapaneseUnexamined Patent Publication has as its objective to reduce the sideeffects of adrenocortical hormones by lowering their doses (or theirconcentration in a preparation) by combining them with another, adjuvantmolecule, and it does not describe a method of directly reducing theside effects of adrenocortical hormones not by reducing their dose (ortheir concentration in a preparation).

In contrast, the present inventors surprisingly found that those twocompounds, when concurrently administered, exhibit synergism of theantiinflammatory effects of the respective agents as opposed to simpleaddition of their effects and simultaneously found unexpectedly that theside effects of the adrenocortical hormones are directly reducedremarkably without requiring to lower their dose (or their concentrationin a preparation). No agent has been known before that can directly andremarkably reduce the side effects of adrenocortical hormones withoutaltering the doses (or the concentration in a preparation) ofadrenocortical hormones, as opposed to reducing their side effect bylowering their doses (or their concentration in a preparation) bycombining them with another, adjuvant molecule. Thus, the invention isan epoch-making discovery.

For the purpose of the present invention, the present compound used fora medicament for reducing side effects of adrenocortical hormones may beused in its free form or in the form of a pharmacologically acceptablesalt thereof. Examples of such pharmacologically acceptable saltsinclude, but are not limited to, alkaline metal salts such as sodiumsalt, potassium salt and the like, and alkaline earth metal salts suchas calcium salt, magnesium salt and the like. Other salts may be usedinsofar as they are pharmacologically acceptable.

The medicament for reducing side effects of adrenocortical hormones ofthe present invention may contain one species of the present compound ortwo or more of its species in combination, according to a given purposeand need.

As it has very low toxicity and thus is highly safe, the presentcompound for the medicament for reducing side effects of adrenocorticalhormones of the present invention can be used advantageously for thepurpose of the present invention. [For example, a potassium salt ofphosphodiester of L-ascorbic acid and DL-α-tocopherol (a compoundwherein both R₁ and R₂ denote methyl, hereinafter referred to as“EPC-K”), a representative species of the present compound, has LD₅₀values of over 5 g/kg (rat), p.o., and over 100 mg/kg (rat), i.v.]

The medicament for reducing side effects of adrenocortical hormones ofthe present invention may contain further ingredients having otherpharmacological effects insofar as they does not contradict the purposeof the present invention.

The medicament for reducing side effects of adrenocortical hormones ofthe present invention may be used either orally or parenterally (e.g.,by intravenous injection, subcutaneous injection, intramuscularinjection, or intravenous drip). As for pharmaceutical preparationforms, it may be formed either into solid preparations includingtablets, granules, powders, capsules and ointment, or into liquidpreparations including injections, oral liquid preparations and eyedrops, by known methods. For those preparations, conventional additivesmay be employed such as excipients, binders, disintegrants, dispersingagents, resorption enhancers, buffering agents, surfactants,solubilizers, preservatives, emulsifiers, isotonizers, stabilizers, pHadjusting agents and the like.

The medicament for reducing side effects of adrenocortical hormones ofthe present invention may be a pharmaceutical preparation comprising amixture of an adrenocortical hormone and the present compound, or therespective components may be administered separately. The concentrationof the adrenocortical hormone and the present compound in the mixturepreparation is usually about 0.001%-about 1%, preferably about 0.01%to-about 0.5% for the adrenocortical hormone and about 1-about 100 times(weight ratio), preferably about 1-about 50 times (weight ratio) theamount thereof for the present compound, although it may vary inaccordance with the species of the present compound and the specificadrenocortical hormone employed as well as with the form of thepreparation. When an adrenocortical hormone and the present compound isadministered separately, the dose for the present compound is about 1mg-about 100 mg, preferably about 1 mg-about 50 mg per 1 mg of anadrenocortical hormone, although it may vary in accordance with thespecies of the present compound and the specific adrenocortical hormoneemployed, as well as with the age, body weight, sex, symptoms to beaddressed and the form of the preparation. The present compound isadministered at doses of about 0.5-about 200 mg, preferably about2-about 50 mg per day for adult in the case of injections, at doses ofabout 5-about 2000 mg, preferably about 20-about 500 mg at one time,which is repeated several times a day for adult in the case of oralpreparations, or in several drops at one time, which is repeated severaltimes a day for adult in the case of eye drops whose concentration isabout 0.01 W/V %-about 0.5 W/V %, or is applied several times a day inthe case of ointment whose concentration is about 0.01 W/W %-about 5 W/W%.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in further detail below withreference to examples and preparation examples. It should be noted,however, that the present invention is not limited by those examples.

EXAMPLE 1 Effect of the Present Compound to Reduce Side Effects of anAdrenocortical Hormone

A test was carried out to examine the effect of the present compound toreduce side effects of an adrenocortical hormone.

(Test materials)

0.012% betamethasone valerate (dissolved in methanol).

0.012% betamethasone valerate +0.5% EPC-K (dissolved in methanol).

(Test method)

10-week old female HR-1 hairless mice purchased from SLC Japan were usedfor the test. One hundred μl of the test materials were applied to therespective mice on the whole area of their back skin. This procedure wasrepeated once a day for two weeks, and then the body weight and theweight of the thymus and the spleen were determined.

(Results)

Tables 1-3 show the rates of body weight increase and the weight of thethymus and the spleen determined two weeks after the application of thetest materials.

TABLE 1 Rate of body weight increase Rate (%) of body weight Testmaterials increase 0.012% Betamethasone valerate −7.4 ± 2.2 0.012%Betamethasone valerate + 0.5% EPC-K −4.4 ± 2.3 Normal (no application)−1.0 ± 2.6 The figures indicate mean ± S.D. (n = 6-7).

TABLE 1 Rate of body weight increase Rate (%) of body weight Testmaterials increase 0.012% Betamethasone valerate −7.4 ± 2.2 0.012%Betamethasone valerate + 0.5% EPC-K −4.4 ± 2.3 Normal (no application)−1.0 ± 2.6 The figures indicate mean ± S.D. (n = 6-7).

TABLE 1 Rate of body weight increase Rate (%) of body weight Testmaterials increase 0.012% Betamethasone valerate −7.4 ± 2.2 0.012%Betamethasone valerate + 0.5% EPC-K −4.4 ± 2.3 Normal (no application)−1.0 ± 2.6 The figures indicate mean ± S.D. (n = 6-7).

As clearly shown in Tables 1-3,the body weight reduction and the atrophyof thymus and spleen were suppressed by EPC-K administered concurrentlywith betamethasone valerate, demonstrating the effect of EPC-K to reduceside effects of the steroid. Thus the present compound was found to beuseful as a medicament for reducing the side effects of adrenocorticalhormones.

Reference Example Synergism of Effects of the Present Compound and anAdrenocortical Hormone (antiinflammatory effect)

A test was performed for examining antiinflammatory effect observed byconcurrent use of the present compound and an adrenocortical hormone. Inaddition, dose-response test was carried out for the adrenocorticalhormone.

(Test materials)

0.012% betamethasone valerate (dissolved in methanol).

0.5% EPC-K (dissolved in methanol).

0.012% betamethasone valerate +0.5% EPC-K (dissolved in methanol).

(Test method)

10-week old male ICR mice purchased from SLC Japan were used for thetest. Twenty μl of croton oil (6%) dissolved in acetone was applied onthe outer surface of the right auricles of the mice to induce edema.Fifteen minutes later, 20 μl of one of the test materials was applied toeach of the right auricles.

Four hours after the application of the test materials, the thickness ofthe right auricles of the mice were measured using a dial thicknessgauge and edema rates were determined by comparing their thickness withthat before induction.

(Results)

The results are shown in Tables 4-5.

TABLE 4 Synergism of the effects of the present compound andbetamethasone valerate Test materials Edema rate(%) Inhibition rate(%)Methanol 116.1 ± 23.3 — 0.5% EPC-K 109.1 ± 26.3  6.0 0.012%Betamethasone valerate  87.3 ± 21.7 27.9 0.012% Betamethasone valerate + 55.5 ± 20.4* 52.2 0.5% EPC-K The figures indicate mean ± S.D. (n =23-27). Significant difference from 0.012% betamethasone valerate or0.5% EPC-K: *¹; p < 0.0.001

TABLE 5 Dose-response test of betamethasone valerate Test materialsEdema rate(%) Inhibition rate(%) Methanol 138.8 ± 18.5 — 0.012%Betamethasone valerate 101.6 ± 15.3 26.8 0.040% Betamethasone valerate 86.5 ± 30.3 37.7 0.12% Betamethasone valerate  52.8 ± 13.3 62.0 Thefigures indicate mean ± S.D. (n = 8-9).

As clearly shown in Table 4,the concurrent use of the present compoundand the steroid exhibited synergism of the effects compared with theresults of their single use.

Based on the result of the dose-response test (Table 5), a calculationrevealed that 0.088% of betamethasone valerate would give an effectcomparable to the effect obtained by 0.012% betamethasone valerate plus0.5% EPC-K.

[Preparation Example 1] Oral tablets EPC-K 100 mg  Lactose 75 mg Starch20 mg Polyethylene glycol 6000  5 mg

The above components are admixed by a conventional method to form atablet. Sugar coating may be applied as needed.

[Preparation Example 2] Injection EPC-K 200 mg Mannitol 5.0 g 1N Sodiumhydroxide q.s. Distilled water to 100 ml pH 6.5

The above component are admixed to dissolve by a conventional method andthe solution is aseptically filtered. The filtrate is asepticallyintroduced 5-ml each into glass ampoules, which then are heat-sealed toprovide an injection.

[Preparation Example 3] Ointment Hydrocortisone 100 mg EPC-K 1.0 gHydrophilic ointment to 100 g

The ointment is made by a conventional method.

[Preparation Example] Eye drops Sodium dexamethasone meta-sulfobenzoate10 mg EPC-K 0.2 g Glycerol 2.6 g Methyl p-benzoate 0.14 g Propylp-benzoate 0.16 g Sodium hydrogen phosphate 0.1 g Acetic acid q.s.Distilled water to 100 ml pH 6.5

The eye drops is made by a conventional method.

INDUSTRIAL APPLICABILITY

The pharmaceutical preparations of the present invention is useful asmedicaments for reducing side effects of adrenocortical hormones, forthey can directly and remarkably reduce the side effects ofadrenocortical hormones without requiring reduction of their doses.

What is claimed is:
 1. A method for reducing side effects caused by anadrenocortical hormone in a patient treated therewith, which methodcomprises administering to the patient in need thereof a phosphodiestercompound of the following formula to a pharmacologically acceptable saltthereof in an amount sufficient to reduce side effects caused by anadrenocortical hormone

wherein R₁ and R₂ are the same or different and each denotes hydrogen ormethyl.
 2. The method according to claim 1, wherein the phosphodiesteror a pharmacologically acceptable salt thereof and the adrenocorticalhormone are administered in a ratio of 1-100 mg of the phosphodiestercompound or a pharmacologically acceptable salt thereof to 1 mg ofadrenocortical hormone.
 3. The method according to claim 1, wherein thephosphodiester compound or a pharmacologically acceptable salt thereofis administered to treat side effects of an adrenocortical hormoneselected from the group consisting of betamethasone valerate,hydrocortisone, sodium dexamethasone meta-sulfobenzoate, triamcinoloneacetonide, alclometasone propionate, and fluocinolone acetonide.
 4. Themethod according to claim 1, wherein the phosphodiester compound or apharmacologically acceptable salt thereof is administered concurrentlywith the adrenocortical hormone.
 5. A method for reducing side effectscaused by an adrenocortical hormone in a patient treated therewith,which method comprises administering to the patient in need thereof apotassium salt of a phosphodiester compound of the following formula inan amount sufficient to reduce side effects caused by the adrenocorticalhormone,

wherein each of R₁ and R₂ denotes methyl.
 6. The method according toclaim 5, wherein the potassium salt of a phosphodiester compound and theadrenocortical hormone are administered in a ratio of 1-100 mg of thepotassium salt to 1 mg of the adrenocortical hormone.
 7. The methodaccording to claim 5, wherein the potassium salt of a phosphodiestercompound is administered to treat side effects of an adrenocorticalhormone selected from the group consisting of betamethasone valerate,hydrocortisone, sodium dexamethasone meta-sulfobenzoate, triamcinoloneacetonide, alclometasone propionate, and fluocinolone acetonide.
 8. Themethod according to claim 5, wherein the potassium salt of aphosphodiester compound is administered concurrently with theadrenocortical hormone.